Project Summary: Recent clinical studies have suggested that elevated levels of circulating stem cells may decrease the risk of death from cardiovascular disease. Aging has been linked to decreased stem cell functional capacity under conditions of stress, a lower number of circulating stem cells, and an attenuation of the stress induced increase in these circulating cells. In addition, the use of human embryonic stem cells (ESCs) has been faced with tremendous controversy. Therefore adult bone marrow mesenchymal stem cells (aBMSCs) and ESCs may not be optimal for stem cell transplantation after cardiac injury. BMSCs from younger hosts, such as neonates (nBMSC), may be better equipped to survive during conditions of ischemia, and may provide a greater degree of protection during I/R injury. Our hypothesis therefore, is that nBMSCs will provide greater protection to injured myocardium during I/R induced injury. To make significant advancements toward this goal, we propose the following four specific aims: 1) To determine whether nBMSCs exhibit higher levels of protective growth factors and lower levels of proinflammatory cytokines compared to aBMSCs. 2) To determine whether nBMSCs have a higher rate of proliferation, higher pluripotent potential, or increased levels of activated p38, ERK, JNK, or Akt that contribute to the differences observed in cytokine production. 3) To determine whether nBMSCs confer a greater degree of cardioprotection during I/R injury as measured via isolated Langendorff preparation. 4) To determine whether nBMSCs provide greater cardioprotection by decreasing cellular apoptosis via upregulation of the PI3/Akt, SOCS3 or STATS signaling cascades. Relevance to public health: Stem cells may be a new treatment to help patient's who suffer from many different diseases. Understanding the ways that stem cells help patients will allow scientists to create "super" stem cells that both survive better in stressful conditions and release protective growth substances.